My laboratory continues to investigate the bicyclo[3.1.0]hexane template as a platform for the construction of novel conformationally locked carbocyclic nucleosides. We use these modified nucleosides with the purpose of (1) determining the conformational preferences of enzymes involved in the biochemistry of nucleosides, nucleotides, and oligonucleotides; and (2) developing selected compounds as possible antitumor/antiviral drugs based on our understanding of their biochemical mechanism of action. The application of this knowledge has been successfully applied to the design and synthesis of nucleoside analogues directed to precise therapeutic targets such as Kaposi sarcoma virus, HIV, herpes and more recently pox viruses. The effect of chemically synthesized North-methanocarba nucleoside 5'-triphosphates as delay chain terminators of HIV reverse transcriptase and their ability to overcome the excision mechanism of HIV resistance prompted the synthesis of several new analogues capable of circumventing their principal limitation, which is their inability to be activated (phosphorylated) by cellular kinases. Two lines of investigation have been pursued and some of the major findings are highlighted: (1) the successful synthesis of isomeric N-methanocarbathymidine analogues where both the fusion site of the cyclopropane ring and the critical 3'-OH group were relocated to facilitate recognition by kinases. This approach resulted in a 2-fold increase in the formation of all three metabolites (mono-, di- and triphosphates) catalyzed by the herpes thymidine/thymidylate kinase and the cellular diphosphate kinase; and (2) the discovery of a compound, D-Carba dT (carbocyclic thymidine), which is phosphorylated well enough by cellular thymidine kinase to be effective in blocking the replication of wild-type and multi-drug resistant HIV-1 vectors in cultured cells. North-methanocarbathymidine (N-MCT) has been licensed and it is targeted for development as an antiviral agent against Kaposi sarcoma, herpes simplex 1 and 2, and pox. A recent review published in Antiviral Research highlights the history and discovery of N-MCT. The studies on DNA bending continued with the completion of a comprehensive study describing the contrasting behavior and annealing properties of antipodal North- and South-containing olidodeoxynucleotides that will soon be published.